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Objectives: To study differences regarding pain and activity limitations during the 3 years following diagnosis in women and men with contemporary treated early RA compared with their counterparts who were diagnosed 10 years earlier. Method: This study was based on patients recruited to the Early Intervention in RA (TIRA) project. In the first cohort (TIRA-1) 320 patients were included in time for diagnosis during 1996-1998 and 463 patients were included in the second cohort (TIRA-2) during 2006-2009. Disease activity, pain intensity (Visual Analogue Scale, VAS), bodily pain (BP) in the 36-item Short Form Health Survey (SF-36), activity limitations (Health Assessment Questionnaire, HAQ), and medication were reported at inclusion and at follow-up after 1, 2, and 3 years. Results: Disease activity, pain, and activity limitations were pronounced at inclusion across both genders and in both cohorts, with some improvement observed during the first year after diagnosis. Disease activity did not differ between cohorts at inclusion but was significantly lower at the follow-ups in the TIRA-2 cohort, in which the patients were prescribed traditional disease-modifying anti-rheumatic drugs (DMARDs) and biological agents more frequently. In TIRA-2, patients reported significantly lower pain and activity limitations at all follow-ups, with men reporting lower pain than women. Women reported significantly higher activity limitations at all time points in TIRA-2. Conclusions: Pain and activity limitations were still pronounced in the contemporary treated early RA cohort compared with their counterparts diagnosed 10 years earlier and both of these factors need to be addressed in clinical settings.

This study aimed to examine the difficulties with performing valued life activities in relation to pain intensity in women and men with rheumatoid arthritis (RA). In total, 737 persons with RA (73 % women) from three rheumatology units in Sweden responded to a questionnaire measuring performance of 33 valued life activities and self-rated pain. The relationships between performance of valued life activities (VLAs) and pain (measured by visual analogue scale (VAS)) were analysed based on gender. Multiple linear regression analyses were conducted with the total VLA score as dependent variable. Women reported more pain and difficulties in performing valued life activities than men. Across genders, 85 % reported at least one valued life activity affected by RA. Significantly more women than men encountered difficulties in performing some activities such as cooking, gardening and meeting new people. Women reported higher pain intensity (35 mm) than men (31 mm). Almost all 33 difficulty ratings for valued life activities were higher among persons with high pain (greater than 40 mm) than persons with lower pain. Difficulty ratings for valued life activities correlated positively with pain in persons with lower pain, but not among those with high pain. The results highlight the importance of addressing pain, especially among women with RA, as they reported pain to impact on their valued life activities. Interestingly, this was evident also in women with lower levels of pain.

OBJECTIVE: To study whether personal factors (self-efficacy and pain acceptance) mediate the relationship between pain and performance of valued life activities in persons with rheumatoid arthritis.

METHODS: Persons with rheumatoid arthritis for at least four years (n = 737; 73% women) answered a questionnaire measuring self-efficacy, pain acceptance, performance of valued life activities, and self-rated pain. Relationships among these constructs were explored using univariate and multivariate analyses. Structural equation modelling was then used to examine the mediational role of personal factors on the relationship between pain and performance of valued life activities.

RESULTS: A direct negative association between pain and performance of valued life activities was identified (Beta = .34, P < .001). This suggests that people with rheumatoid arthritis who had higher levels of pain has increased difficulties in performing valued life activities. Self-efficacy and activity engagement component of pain acceptance mediated the relationship between pain and performance of valued life activities, however the pain willingness component of pain acceptance did not influence participation in valued life activities.

CONCLUSION: These findings highlight the importance of considering personal factors, such as pain acceptance and self-efficacy, in facilitating participation in valued life activities.

Objective: To explore how demographics, pain, psychosocial factors and insomnia relate to the spread of chronic pain. Methods: The study included 708 patients (68% women; median age 46 years; interquartile range 3557 years) with chronic pain who were referred to a multidisciplinary pain centre. Spreading of pain was assessed using a questionnaire covering 36 anatomically predefined pain regions. Data were collected on demographics, pain symptoms, psychological distress, and insomnia (Insomnia Severity Index). Four sub-categories of chronic pain were established: chronic local pain, chronic regional pain medium, chronic regional pain heavy, and chronic widespread pain. Results: The median number of pain regions was 10 (interquartile range 6-18). Prevalence of chronic pain was as follows: chronic local pain 9%, chronic regional pain medium 21%, chronic regional pain heavy 39%, and chronic widespread pain 31%. In the regression models, being a woman and persistent pain duration had the strongest associations with spreading of pain, but anxiety, pain interference, and insomnia were also important factors. Conclusion: Spreading of chronic pain can only partly be explained by the simultaneous levels of insomnia. Female sex, pain duration, pain interference and anxiety appear to have more significant relationships with the spread of pain. Targeting these factors may lead to improvements in treatment and prevention strategies.

Background: Little is known about whether individuals with autism spectrum disorder (ASD) or attention deficit hyperactive disorder (ADHD) experience any specific facilitators or barriers to driving education. Objective: To explore the facilitators or barriers to driving education experienced by individuals with ASD or ADHD who obtained a learners permit, from the perspective of the learner drivers and their driving instructors. Methods: Datawere collected from33 participants with ASD or ADHD, and nine of their driving instructors. Results: Participants with ASD required twice asmany driving lessons andmore on-road tests than those with ADHD. Participants with ADHD repeated the written tests more than those with ASD. Driving license theory was more challenging for individuals with ADHD, whilst individuals with ASD found translating theory into practice and adjusting to "unfamiliar driving situations to be the greatest challenges. Conclusion: Obtaining a driving license was associated with stressful training experience.

Purpose: Methods for delivering aftercare to help chronic pain patients to continue practice self-management skills after rehabilitation are needed. Internet-delivered cognitive behavioral therapy (ICBT) has the potential to partly fill this gap given its accessibility and emphasis on self-care. Methods for engaging and motivating patients to persist throughout the full length of treatment are needed. The aim of this study was to describe how chronic pain patients work in an ICBT program, through their descriptions of what is important when they initiate behavior change in aftercare and their descriptions of what is important for ongoing practice of self-management skills in aftercare. Patients and methods: Following a multimodal rehabilitation program, 29 chronic pain patients participated in a 20-week-long Internet-delivered aftercare program (ACP) based on acceptance-based cognitive behavioral therapy. Latent content analysis was made on 138 chapters of diary-like texts written by participants in aftercare. Results: Attitudes regarding pain and body changed during ACP, as did attitudes toward self and the future for some participants. How participants practiced self-management skills was influenced by how they expressed motivation behind treatment goals. Whether they practiced acceptance strategies influenced their continuous self-management practice. Defusion techniques seemed to be helpful in the process of goal setting. Mindfulness strategies seemed to be helpful when setbacks occurred. Conclusion: Self-motivating goals are described as important both to initiate and in the ongoing practice of self-management skills. Experiencing a helpful effect of acceptance strategies seems to encourage participants to handle obstacles in new ways and to persist throughout treatment. Research on whether tailored therapist guidance might be helpful in stating self-motivating goals and contribute to ongoing practice of self-management skills is needed.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease often associated with disability. Despite new treatments, pain and activity limitations are still present. Objectives: To describe how persons with RA experience and manage pain in their daily life. Methods: Seven semi-structured focus groups (FGs) were conducted and analyzed using content analysis. Results: The analysis revealed four categories: 1) Pain expresses itself in different ways referred to pain as overwhelming, aching or as a feeling of stiffness. 2) Mitigating pain referred to the use of heat, cold, medications and activities as distractions from the pain. 3) Adapting to pain referred to strategies employed as coping mechanisms for the pain, e.g. planning and adjustment of daily activities, and use of assistive devices. 4) Pain in a social context referred to the participants social environment as being both supportive and uncomprehending, the latter causing patients to hide their pain. Conclusions: Pain in RA is experienced in different ways. This emphasizes the multi-professional team to address this spectrum of experiences and to find pain management directed to the individual experience that also include the persons social environment.

Quality-adjusted life years (QALYs) measure health by combining length and quality of life. QALYs constitute the effect side of incremental cost-effectiveness ratios, describing the results of health economic evaluations. The objectives of this study were to (1) investigate the prevalence of states worse than dead (SWD) when using the EuroQol-5D UK value set, and (2) to study to what extent SWDs are reasonable with a starting point in experience-based valuations of health states. Data from a Swedish cross-sectional population survey were used. The survey was directed to 10,000 persons 65 years and older and its primary aim was to investigate the prevalence and consequences of chronic pain. The survey included questions reflecting life situation and well-being. Some of these were used in order to characterise people in SWD. SWD were found in 1.8% of the 6611 respondents. The prevalence of SWD increased with advancing age and was more common among women than men. The control questions used indicated that most of the persons being in SWD according to the EQ-5D UK value set most probably would not judge themselves to be in a SWD. Though negative QALY-weights are not very common, they constitute a non-negligible part of health states in a Swedish population 65 years and older. Prevalence of SWD is higher among women than men and increases with age. From responses to other questions on well-being and life situation, there is reason to doubt the reasonableness of experience-based negative QALY-weights in many cases.

Chronic pain among elderly people has long been a well-known problem, in terms of both societal costs and the quality of life of affected individuals. To estimate the magnitude of the problems associated with chronic pain in an elderly population, data on both costs and quality of life were gathered. A postal questionnaire was sent out to a stratified sample of 10 000 inhabitants 65 years and older in Linköping and Norrköping. The survey included questions on demographics, habits, and life situation, and different kinds of questions and instruments related to well-being (e.g., quality-of-life and pain-specific questions). In the questionnaire respondents were asked whether they were receiving any help—informal care—from a relative. If they answered yes, they were asked for permission to contact the informal caregiver and to provide contact details. The amount of informal care provided by relatives to persons with chronic pain was investigated by use of a questionnaire directed to the caregiving relatives, containing questions about time spent providing informal care.

Data on costs were collected from registers of consumption of health care, drugs, and municipal services.

The results of the study showed a very clear association between existence and severity of chronic pain and societal costs. The study population was subdivided into three groups with respect to having chronic pain or not, and a pain intensity during the last week of 0–4 (mild), 5–7 (moderate), or 8–10 (severe) on a scale of 0–10. Taking all costs (health care, drugs, municipal services, and informal care) into account, persons in the severe chronic pain group consumed on average 72% more resources than persons in the moderate chronic pain group and 143% more than those in the no or mild chronic pain group. Differences were most pronounced concerning municipal services and informal care costs.

Even more alarming are the results on the quality of life of persons in the different groups. On the EQ-5D index, the average value for persons in the no or mild chronic pain group was 0.82. For those in the moderate chronic pain group the average value was 0.64, and for those in the severe chronic pain group the average value was only 0.38. EQ-VAS resulted in less pronounced but still clearly significant differences.

It is concluded that this study, reaching a rather large part of the target population, shows that existence and severity of chronic pain among people 65 years and older affects costs to society and the quality of life of affected individuals in a massive way.

Chronic pain is associated with large societal costs, but few studies have investigated the total costs of chronic pain with respect to elderly subjects. The elderly usually require informal care, care performed by municipalities, and care for chronic diseases, all factors that can result in extensive financial burdens on elderly patients, their families, and the social services provided by the state. This study aims to quantify the societal cost of chronic pain in people of age 65 years and older and to assess the impact of chronic pain on quality of life. This study collected data from 3 registers concerning health care, drugs, and municipal services and from 2 surveys. A postal questionnaire was used to collect data from a stratified sample of the population 65 years and older in southeastern Sweden. The questionnaire addressed pain intensity and quality of life variables (EQ-5D). A second postal questionnaire was used to collect data from relatives of the elderly patients suffering from chronic pain. A total of 66.5% valid responses of the 10,000 subjects was achieved; 76.9% were categorized as having no or mild chronic pain, 18.9% as having moderate chronic pain, and 4.2% as having severe chronic pain. Consumed resources increased with the severity of chronic pain. Clear differences in EQ-5D were found with respect to the severity of pain. This study found an association between resource use and severity of chronic pain in elderly subjects: the more severe the chronic pain, the more extensive (and expensive) the use of resources.

Objectives: Patients with an implanted spinal cord stimulation (SCS) system for pain management present an opportunity to study dynamic changes in the pain system in a situation where patients are not stimulated (ie, experiencing severe pain) compared with a situation in which patients have just been stimulated (ie, pain free or greatly reduced pain). The aims of this study were (1) to determine if there are differences in nociceptive withdrawal reflex thresholds (NWR-T) and electrical pain thresholds (EP-T) before and after SCS; and (2) to establish if these differences are related to psychological factors associated with chronic pain. Methods: Seventeen volunteers with chronic neuropathic pain participated in the experiment. Electrical stimuli were applied to assess the NWR-T and the EP-T. In addition, psychological factors (ie, pain characteristics, depression, anxiety, and disability indexes) were also recorded. The NWR-T and EP-T were assessed with the SCS system off (at least 8 h before the experiment), and then reassessed 1 hour after the SCS system was turned on. Results: Ongoing pain intensity ratings decreased (P=0.018), whereas the NWR-T increased (P=0.028) after the SCS was turned on, whereas no significant difference was found for EP-T (P=0.324). Psychological factors were significant predictors for EP-T but not for NWR-T. Discussion: The results of this study suggest that pain relief after SCS is partially mediated by a decrease in the excitability of dorsal horn neurons in the spinal cord.

Background: Chronic pain and fatigue improves by exercise in fibromyalgia (FM) but underlying mechanisms are not known. Obesity is increased among FM patients and associates with higher levels of pain. Symptom improvement after aerobic exercise is affected by body mass index (BMI) in FM. Metabolic factors such as insulin-like growth factor 1 (IGF1) and leptin may be involved. In this study, the aim was to evaluate the role of metabolic factors in lean, overweight and obese women during resistance exercise, in relation to symptom severity and muscle strength in women with FM. Methods: Forty-three women participated in supervised progressive resistance exercise, twice weekly for 15-weeks. Serum free and total IGF-1, IGF-binding protein 3 (IGFBP3), adiponectin, leptin and resistin were determined at baseline and after 15-weeks. Level of current pain was rated on a visual analogue scale (0-100 mm). Level of fatigue was rated by multidimensional fatigue inventory (MFI-20) subscale general fatigue (MFIGF). Knee extension force, elbow flexion force and handgrip force were assessed by dynamometers. Results: Free IGF-1 (p = 0.047), IGFBP3 (p = 0.025) and leptin (p = 0.008) were significantly decreased in lean women (n = 18), but not in the overweight (n = 17) and the obese (n = 8). Lean women with FM benefited from resistance exercise with improvements in current pain (p= 0.039, n = 18), general fatigue (MFIGF, p = 0.022, n = 18) and improved elbow-flexion force (p = 0.017, n = 18). In overweight and obese women with FM there was no significant improvement in pain or fatigue but an improvement in elbow flexion (p = 0.049; p = 0.012) after 15 weeks of resistance exercise. Conclusion: The clearest clinical response to resistance exercise was found in lean patients with FM. In these individuals, individualized resistance exercise was followed by changes in IGF-1 and leptin, reduced pain, fatigue and improved muscular strength. In overweight and obese women FM markers of metabolic signaling and clinical symptoms were unchanged, but strength was improved in the upper limb. Resistance exercise combined with dietary interventions might benefit patients with FM and overweight.

Background: Safe driving is a complex activity that requires calibration. This means the driver can accurately assess the level of task demand required for task completion and can accurately evaluate their driving capability. There is much debate on the calibration ability of post-stroke drivers. Objectives: The aim of this study was to assess the cognition, self-rated performance, and estimation of task demand in a driving simulator with post-stroke drivers and controls. Methods: A between-groups study design was employed, which included a post-stroke driver group and a group of similarly aged older control drivers. Both groups were observed driving in two simulator-based driving scenarios and asked to complete the NASA Task Load Index (TLX) to assess their perceived task demand and self-rate their driving performance. Participants also completed a battery of psychometric tasks to assess attention and executive function, which was used to determine whether post-stroke cognitive impairment impacted on calibration. Results: There was no difference in the amount of perceived task demand required to complete the driving task. Despite impairments in cognition, the post-stroke drivers were not more likely to over-estimate their driving abilities than controls. On average, the post-stroke drivers self-rated themselves more poorly than the controls and this rating was related to cognitive ability. Conclusion: This study suggests that post-stroke drivers may be aware of their deficits and adjust their driving behavior. Furthermore, using self-performance measures alongside a driving simulator and cognitive assessments may provide complementary fitness-to-drive assessments, as well as rehabilitation tools during post-stroke recovery.

Driving is an important activity of daily living, which is increasingly relied upon as the population ages. It has been well-established that cognitive processes decline following a stroke and these processes may influence driving performance. There is much debate on the use of off-road neurological assessments and driving simulators as tools to predict driving performance; however, the majority of research uses unlicensed poststroke drivers, making the comparability of poststroke adults to that of a control group difficult. It stands to reason that in order to determine whether simulators and cognitive assessments can accurately assess driving performance, the baseline should be set by licenced drivers. Therefore, the aim of this study was to assess differences in cognitive ability and driving simulator performance in licensed community-dwelling poststroke drivers and controls. Two groups of licensed drivers (37 poststroke and 43 controls) were assessed using several cognitive tasks and using a driving simulator. The poststroke adults exhibited poorer cognitive ability; however, there were no differences in simulator performance between groups except that the poststroke drivers demonstrated less variability in driver headway. The application of these results as a prescreening toolbox for poststroke drivers is discussed.

Driving is a highly complex task requiring multiple cognitive processes that can be adversely affected post-stroke. It is unclear how much ability post-stroke adults have to self-evaluate their driving performance. Furthermore, the impact of cognitive decline on this evaluation has not been previously investigated. The aim of this study was to investigate the perceived level of task demand involved in driving tasks, and to examine differences between perceived and observed driving performance in post-stroke drivers in comparison to a control group. A further aim of the research was to investigate the influence of cognition on self-rated driving performance. A total of 78 participants (35 post-stroke and 43 controls) were assessed using a series of cognitive tasks and were observed whilst driving. Participants were asked to rate their own driving performance and the task demand involved while driving using the NASA Task Load Index. Between group analyses were conducted to determine differences in the level of self-rated performance and task demand. Further analyses were conducted to investigate whether cognition accounted for differences in task demand or self-rated performance. Overall, the results suggested that the post-stroke drivers exhibited deficits in cognition, but they did not report increased levels of task demand when driving. Post-stroke adults also rated themselves more conservatively than the controls for on-road performance, which was associated with their reduced propensity for risk. The study suggests that cognitive deficits may influence post-stroke drivers to amend their driving behaviour, in order to bring the task demand within a manageable level. Understanding the mechanisms involved in self-rated performance and estimations of task demand can help promote accurate self-regulation practices in post-stroke drivers. Furthermore, measuring calibration may assist practitioners with assessing fitness-to-drive, as well as with tailoring driving rehabilitation.

Objective: To establish the impact of a gaze-based assistive technology (AT) intervention on activity repertoire, autonomous use, and goal attainment in children with severe physical impairments, and to examine parents’ satisfaction with the gaze-based AT and with services related to the gaze-based AT intervention.

Methods: Non-experimental multiple case study with before, after, and follow-up design. Ten children with severe physical impairments without speaking ability (aged 1–15 years) participated in gaze-based AT intervention for 9–10 months, during which period the gaze-based AT was implemented in daily activities.

Results: Repertoire of computer activities increased for seven children. All children had sustained usage of gaze-based AT in daily activities at follow-up, all had attained goals, and parents’ satisfaction with the AT and with services was high.

Discussion: The gaze-based AT intervention was effective in guiding parents and teachers to continue supporting the children to perform activities with the AT after the intervention program.

Gaze-based assistive technology (gaze-based AT) has the potential to provide children affected by severe physical impairments with opportunities for communication and activities. This study aimed to examine changes in eye gaze performance over time (time on task and accuracy) in children with severe physical impairments, without speaking ability, using gaze-based AT. A longitudinal study with an AB design was conducted on ten children (aged 1–15 years) with severe physical impairments, who were beginners to gaze-based AT at baseline. Thereafter, all children used the gaze-based AT in daily activities over the course of the study. Compass computer software was used to measure time on task and accuracy with eye selection of targets on screen, and tests were performed with the children at baseline, after 5 months, 9–11 months, and after 15–20 months. Findings showed that the children improved in time on task after 5 months and became more accurate in selecting targets after 15–20 months. This study indicates that these children with severe physical impairments, who were unable to speak, could improve in eye gaze performance. However, the children needed time to practice on a long-term basis to acquire skills needed to develop fast and accurate eye gaze performance.

Background: Young drivers with Attention Deficit Hyperactivity Disorder (ADHD) are at higher risk of road traffic injuries than their peers. Increased risk correlates with poor hazard perception skill. Few studies have investigated hazard perception training using computer technology with this group of drivers. Objectives: *Determine the presence and magnitude of the between-group.and within- subject change in hazard perception skills in young drivers with ADHD who receive Drive Smart training. *Determine whether training facilitated change in hazard perception is maintained over time. Methods: This was a feasibility study, randomised control trial conducted in Australia. The design included a delayed treatment for the control group. Twenty-five drivers with a diagnosis of ADHD were randomised to the Immediate Intervention or Delayed Intervention group.The Immediate Intervention group received a training session using a computer application entitled Drive Smart. The Delayed Intervention group watched a documentary video initially (control condition), followed by the Drive Smart computer training session. The participants hazard perception skill was measured using the Hazard Perception Test (HPT). Findings: After adjusting for baseline scores, there was a significant betweengroup difference in post-intervention HPT change scores in favour of the Immediate Intervention group. The magnitude of the effect was large. There was no significant within-group delayed intervention effect. A significant maintenance effect was found at 6 week follow-up for the Immediate Intervention group. Conclusions: The hazard perception skills of participants improved following training with large effect size and some maintenance of gain. A multimodal approach to training is indicated to facilitate maintenance. A full-scale trial is feasible.

Ziconotide is a selective and potent blocker of N-type voltage-gated calcium channels. It was approved by the Food and Drug Administration in 2004 and by the European Medicines Agency in 2005 for the treatment of severe chronic pain in patients needing intrathecal analgesia (ITA). The aim of this paper is to provide a practitioner-oriented, educational, narrative, up-to-date review on the use of ziconotide in clinical pain medicine. Of special concern regarding safety is the partial incongruity between dosing statements in the Summary ofProduct Characteristics and novel low-dosage, slow uptitration recommendations. Even though ziconotide has obvious advantages compared to opioids, pain practitioners pondering the use of ziconotide nonetheless have to balance its proved potential analgesic effect against its neurological side effects, with special consideration being given to dosing and neuropsychiatric dangers. Using a seesaw analogy, the paper discusses what factors pain physicians should weigh in when considering ziconotide as ITA drug, the non-opioid advantages of ziconotide being counterbalanced by its potential psychiatric side effects. Ziconotide is an important part of the armamentarium of modern interventional pain medicine. If ITA is deemed necessary, ziconotide is a rational alternative, at least in chronic (neuropathic) non-cancer pain. However, in many European countries, ziconotide treatment is only available in a few (if any) centres. The safety profile of ziconotide is not fundamentally more worrying than that of opioids or cannabinoids; it is just different. This paper provides a concise, up-to-date and clinically-oriented summary of the use of ziconotide in clinical practice, not least concerning safety and dosage issues.

Chronic pain is highly prevalent, and pain medicine lacks objective biomarkers to guide diagnosis and choice of treatment. The current U.S. "opioid epidemic" is a reminder of the paucity of effective and safe treatment options. Traditional pain diagnoses according to the International Classification of Diseases are often unspecific, and analgesics are often prescribed on a trial-and-error basis. In contrast to this current state of affairs, the vision of future mechanism-based diagnoses of chronic pain conditions is presented in this non-technical paper, focusing on the need for biomarkers and the theoretical complexity of the task. Pain is and will remain a subjective experience, and as such is not objectively measurable. Therefore, the concept of "noci-marker" is presented as an alternative to "pain biomarker", the goal being to find objective, measurable correlates of the pathophysiological processes involved in different chronic pain conditions. This vision entails a call for more translational pain research in order to bridge the gap between clinical pain medicine and preclinical science.

There seems to be a strong cultural expectation among patients for effective pain relief. As a result, physicians often find themselves trying to bridge the gap between the chronic pain patients expectations and harsh biomedical reality. The typology of Emanuel and Emanuel of four models for the patient-physician relationship is used in this article as a conceptual tool to examine the possible roles of physicians in the context of chronic noncancer pain. Their typology is reconceptualized as a "pathway" along which the physician is able to walk more or less far, starting from the "information" end of the path. The other end of the pathway is "caring deliberation." I then propose that, in pain medicine today, consumerism is a powerful incentive for physicians to stay at the information end of the spectrum. Against this background, I discuss the current opioid epidemic in the United States and the need for what has been called a new medical professionalism. I conclude by challenging educators involved in pain medicine continuing professional development to not only design adequate biomedical-educational programs, but also consider issues like professionalism, personal development, critical self-reflection, and the ethics of engaging in caring deliberation with chronic pain patients.

The treatment of both cancer pain and non-cancer chronic pain is still suboptimal. The overall aim of this PhD thesis was to conduct translational pain research at the interface between clinical pain medicine and the field of human proteomics, using the practice of intrathecal analgesia at our institution as a starting point. Hence, the cerebrospinal fluid (CSF) is at the centre of the present dissertation, both as a target for infusing analgesics (Papers I and II – clinical and pharmacological aspects) and as an important biofluid for human biomarker studies (Papers III and IV – proteomic aspects). In Paper I, 28 cases of intrathecal analgesia in cancer patients were prospectively followed. Movement-evoked breakthrough pain remained a major clinical problem throughout the study month despite otherwise successful intrathecal analgesia (defined as good control of spontaneous resting pain paralleled by a marked decrease of concomitant systemic opioid doses). This study therefore illustrates the importance of considering not only spontaneous resting pain but also movement-evoked breakthrough pain.

In Paper II, an expert-based algorithm for trialing the intrathecal analgesic ziconotide by bolus injections was evaluated in an open-label study of 23 patients with chronic neuropathic pain. We found few responders (13%) according to the strict criteria of the algorithm, but ziconotide bolus injection trialing seems feasible. The predictive power of ziconotide bolus trialing remains unclear, and the pharmacological profile of ziconotide (with very slow tissue penetration due to high hydrophilicity) calls the rationale for ziconotide bolus trialing into question.

In Paper III, we found low levels of beta-endorphin in the CSF of chronic neuropathic pain patients (n=15) compared to healthy controls (n=19). We speculate that this might indicate dysfunctional top-down control of nociception. Substance P levels in the CSF did not differ by univariate statistics. In Paper IV, the CSF proteome of 11 patients with chronic neuropathic pain and 11 healthy controls was exploratively studied, combining gel-based proteomics with multivariate data analysis. After eliminating four proteins associated with age, 32 proteins were found to highly discriminate between groups. Among these, the seven proteins having the highest discriminatory power between patients and controls were: one isoform of angiotensinogen, two isoforms of alpha-1-antitrypsin, three isoforms of haptoglobin, and one isoform of pigment epithelium-derived factor.

In conclusion, this PhD thesis demonstrates the fruitfulness of studying the CSF, both as a target for infusing analgesics and as a potential mirror of the neurobiological processes involved in pathological pain conditions. The thesis points to the need for more research into the mechanisms of different pain conditions, in order to hopefully achieve the vision of mechanism-based pain diagnoses.

Abstract [en]

Background: Intrathecal analgesia (ITA) is a valuable treatment option for intractable cancer-related pain. However, the issue of movement-evoked breakthrough pain (BTP) has not been specifically investigated in the ITA setting. The aim of the study was to evaluate the effect of ITA on spontaneous resting pain intensity (SRPI), doses of non-ITA opioids, and specifically on movement-evoked pain intensity (MEPI). less thanbrgreater than less thanbrgreater thanMethods: We prospectively studied 28 consecutive patients who graded SRPI and MEPI on a 0-10 numerical rating scale (NRS) at the time of ITA procedure, after 1 week, and after 1 month. Mild pain was defined as NRS andlt;= 3 and severe pain as NRS andgt;= 7. Concomitant doses of opioids were registered. less thanbrgreater than less thanbrgreater thanResults: After 1 week, no patient had severe SRPI compared with 31% before ITA, and the proportion of patients with mild SRPI had increased from 27% to 76%. Meanwhile, the median daily dose of non-ITA opioids decreased from 575 to 120 mg of oral morphine equivalents. The effect on SRPI and on doses of non-ITA opioids remained essentially unchanged during the study month, but the proportion of patients having severe MEPI did not change significantly: 44% still had severe MEPI after 1 week and 40% after 1 month. less thanbrgreater than less thanbrgreater thanConclusion: Movement-evoked BTP was a major clinical problem throughout the study month despite otherwise successful ITA. Improving the quality of life of patients with intractable cancer-related pain should include developing strategies to better deal with movement-evoked BTP.

Open this publication in new window or tab >>Ziconotide Trialing by Intrathecal Bolus Injections: An Open-Label Non-Randomized Clinical Trial in Postoperative/Posttraumatic Neuropathic Pain Patients Refractory to Conventional Treatment

Abstract [en]

Objectives: The aim of this open-label, non-randomized, clinical trial was to evaluate the feasibility of trialing ziconotide by intrathecal bolus injections. Material and Methods: Twenty-three patients, who had peripheral neuropathic pain refractory to pharmacological treatment and were under consideration for Spinal Cord Stimulation, received up to three ziconotide bolus injections according to a comprehensive algorithm. After a first injection of 2.5g, the patients progressed in the algorithm depending on the presence or absence of pain reduction and significant adverse events. A patient was considered a "responder" if experiencing pain reduction and no significant adverse event on two consecutive occasions at the same dosage. Results: We found a low proportion of responders (13%). However 30% of patients experienced greater than= 30% pain reduction on a least one injection, yielding a number needed to treat of similar to 3 for clinically significant pain relief. Pain intensity changed significantly over time (0-6h) (p = 0.047) after a mean ziconotide dose of 2.75 mu g. Adverse events were as expected, and no serious adverse event occurred. We did not find any statistical association between response to Spinal Cord Stimulation and response to ziconotide. Conclusions: Ziconotide bolus injection trialing seems feasible, but the proportion of responders in the present study was low. Adverse events were as expected, and no serious adverse event occurred. The predictive power of ziconotide bolus trialing remains unclear, and the pharmacological profile of ziconotide (slow tissue penetration due to high hydrophilicity) calls the rationale for bolus trialing into question.

Abstract [en]

Objective

Pain medicine still lacks mechanism-specific biomarkers to guide diagnosis and treatment, and defective top-down modulation is an important factor in the pathophysiology of chronic pain conditions. Using modern analytical tools and advanced multivariate statistical analysis, the aim of this study was to revisit two classical potential biomarkers of pro- and anti-nociception in humans (substance P and beta-endorphin), focusing particularly on the cerebrospinal fluid (CSF).

Samples were taken from CSF and blood, and levels of substance P and beta-endorphin were investigated using a Luminex technology kit.

Results

We found low levels of beta-endorphin in the CSF of neuropathic pain patients (66 ± 11 pcg/mL) compared with healthy controls (115 ± 14 pcg/mL) (P = 0.017). Substance P levels in the CSF did not differ (20 ± 2 pcg/mL, 26 ± 2, P = 0.08). However, our multivariate data analysis showed that belonging to the patient group was associated with low levels of both substances in the CSF. A higher correlation between the levels of beta-endorphin and substance P in CSF was found in healthy controls than in patients (rs = 0.725, P < 0.001 vs rs = 0.574, P = 0.032).

Conclusions

Patients with chronic neuropathic pain due to trauma or surgery had low levels of beta-endorphin in the CSF. We speculate that this could indicate a defective top-down modulation of pain in chronic neuropathic pain. Our results also illustrate the importance of taking a system-wide, multivariate approach when searching for biomarkers.

Abstract [en]

Pain medicine lacks objective biomarkers to guide diagnosis and treatment. Combining two-dimensional gel proteomics with multivariate data analysis by projection, we exploratively analyzed the cerebrospinal fluid of eleven patients with severe peripheral neuropathic pain due to trauma and/or surgery refractory to conventional treatment and eleven healthy controls. Using orthogonal partial least squares discriminant analysis, we identified a panel of 36 proteins highly discriminating between the two groups. Due to a possible confounding effect of age, a new model with age as outcome variable was computed for patients (n=11), and four out of 36 protein spots were excluded due to a probable influence of age. Of the 32 remaining proteins, the following seven had the highest discriminatory power between the two groups: an isoform of angiotensinogen (upregulated in patients), two isoforms of alpha-1-antitrypsin (downregulated in patients), three isoforms of haptoglobin (upregulated in patients), and one isoform of pigment epithelium-derived factor (downregulated in patients). It has recently been hypothesized that the renin–angiotensin system may play a role in the pathophysiology of neuropathic pain, and a clinical trial of an angiotensin II receptor antagonist was recently published. It is noteworthy that when searching for neuropathic pain biomarkers with a purely explorative methodology, it was indeed a renin–angiotensin system protein that had the highest discriminatory power between patients and controls in the present study. The results from this hypothesis-generating pilot study have to be confirmed in larger, hypothesis-driven studies with age-matched controls, but the present study illustrates the fruitfulness of combining proteomics with multivariate data analysis in hypothesis-generating pain biomarker studies in humans.

Background: Post-translational modifications (PTMs) generate a tremendous protein diversity from the similar to 20,000 protein-coding genes of the human genome. In chronic pain conditions, exposure to pathological processes in the central nervous system could lead to disease-specific PTMs detectable in the cerebrospinal fluid (CSF). In a previous hypothesis-generating study, we reported that seven out of 260 CSF proteins highly discriminated between neuropathic pain patients and healthy controls: one isoform of angiotensinogen (AG), two isoforms of alpha-1-antitrypsin (AT), three isoforms of haptoglobin (HG), and one isoform of pigment epithelium-derived factor (PEDF). The present study had three aims: (1) To examine the multivariate inter-correlations between all identified isoforms of these seven proteins; (2) Based on the results of the first aim, to characterize PTMs in a subset of interesting proteins; (3) To regress clinical pain data using the 260 proteins as predictors, thereby testing the hypothesis that the above-mentioned seven discriminating proteins and/or the characterized isoforms/fragments of aim (2) would be among the proteins having the highest predictive power for clinical pain data. Methods: CSF samples from 11 neuropathic pain patients and 11 healthy controls were used for biochemical analysis of protein isoforms. PTM characterization was performed using enzymatic reaction assay and mass spectrometry. Multivariate data analysis (principal component analysis and orthogonal partial least square regression) was applied on the quantified protein isoforms. Results: We identified 5 isoforms of AG, 18 isoforms of AT, 5 isoforms of HG, and 5 isoforms of PEDF. Fragments and glycosylated isoforms of AT were studied in depth. When regressing the pain intensity data of patients, three isoforms of AT, two isoforms of PEDF, and one isoform of angiotensinogen "reappeared" as major results, i.e., they were major findings both when comparing patients with healthy controls and when regressing pain intensity in patients. Conclusions: Altered levels of fragments and/or glycosylated isoforms of alpha-1-antitrypsin might mirror pathophysiological processes in the spinal cord of neuropathic pain patients. In particular, we suggest that a putative disease-specific combination of the levels of two different N-truncated fragments of alpha-1-antitrypsin might be interesting for future CSF and/or plasma biomarker investigations in chronic neuropathic pain.

Pain medicine lacks objective biomarkers to guide diagnosis and treatment. Combining two-dimensional gel proteomics with multivariate data analysis by projection, we exploratively analyzed the cerebrospinal fluid of eleven patients with severe peripheral neuropathic pain due to trauma and/or surgery refractory to conventional treatment and eleven healthy controls. Using orthogonal partial least squares discriminant analysis, we identified a panel of 36 proteins highly discriminating between the two groups. Due to a possible confounding effect of age, a new model with age as outcome variable was computed for patients (n=11), and four out of 36 protein spots were excluded due to a probable influence of age. Of the 32 remaining proteins, the following seven had the highest discriminatory power between the two groups: an isoform of angiotensinogen (upregulated in patients), two isoforms of alpha-1-antitrypsin (downregulated in patients), three isoforms of haptoglobin (upregulated in patients), and one isoform of pigment epithelium-derived factor (downregulated in patients). It has recently been hypothesized that the renin–angiotensin system may play a role in the pathophysiology of neuropathic pain, and a clinical trial of an angiotensin II receptor antagonist was recently published. It is noteworthy that when searching for neuropathic pain biomarkers with a purely explorative methodology, it was indeed a renin–angiotensin system protein that had the highest discriminatory power between patients and controls in the present study. The results from this hypothesis-generating pilot study have to be confirmed in larger, hypothesis-driven studies with age-matched controls, but the present study illustrates the fruitfulness of combining proteomics with multivariate data analysis in hypothesis-generating pain biomarker studies in humans.

Opioid prescription changes in Sweden 2000-2015 In contrast to the well-established »opioid epidemic« in the US, very little is known about how the prescription of opioids in Sweden has developed during the last decade. Aggregated data from the open Statistical database of the Swedish Board of Health and Welfare were analyzed descriptively. The yearly prevalence of opioid prescription did not change 2006-2015, but there were dramatic shifts in the choice of opioids. During this period, dextropropoxyphene was pulled off the market. Tramadol was used by fewer individuals (-54 % over the decade), but dosages expressed as Defined Daily Dose/patient/year (DDD/pat/y) increased (+41 %). In contrast, oxycodone and morphine were used by more individuals (+465 % and +137 %, respectively), but DDD/pat/y decreased during the period (-56% and -54%). Studies on non-aggregated data from available registries are needed to further elucidate the circumstances and possible consequences of these shifts in opioid prescription patterns.

Animal models suggest that chemokines are important mediators in the pathophysiology of neuropathic pain. Indeed, these substances have been called "gliotransmitters," a term that illustrates the close interplay between glial cells and neurons in the context of neuroinflammation and pain. However, evidence in humans is scarce. The aim of the study was to determine a comprehensive cerebrospinal fluid (CSF) inflammatory profile of patients with neuropathic pain. Our hypothesis was that we would thereby find indications of a postulated on-going process of central neuroinflammation. Samples of CSF were collected from 2 cohorts of patients with neuropathic pain (n = 11 and n = 16, respectively) and healthy control subjects (n 5 11). The samples were analyzed with a multiplex proximity extension assay in which 92 inflammation-related proteins were measured simultaneously (Proseek Multiplex Inflammation I; Olink Bioscience, Uppsala, Sweden). Univariate testing with control of false discovery rate, as well as orthogonal partial least squares discriminant analysis, were used for statistical analyses. Levels of chemokines CXCL6, CXCL10, CCL8, CCL11, CCL23 in CSF, as well as protein LAPTGF-beta-1, were significantly higher in both neuropathic pain cohorts compared with healthy controls, pointing to neuroinflammation in patients. These 6 proteins were also major results in a recent similar study in patients with fibromyalgia. The findings need to be confirmed in larger cohorts, and the question of causality remains to be settled. Because it has been suggested that prevalent comorbidities to chronic pain (eg, depression, anxiety, poor sleep, and tiredness) also are associated with neuroinflammation, it will be important to determine whether neuroinflammation is a common mediator.

Objective To subgroup chronic pain patients using psychometric data and regress the variables most responsible for subgroup discrimination. Design Cross-sectional, registry-based study. Setting and subjects Chronic pain patients assessed at a multidisciplinary pain centre between 2008 and 2015. Methods Data from the Swedish quality registry for pain rehabilitation (SQRP) were retrieved and analysed by principal component analysis, hierarchical clustering analysis, and partial least squares-discriminant analysis. Results Four subgroups were identified. Group 1 was characterized by low "psychological strain", the best relative situation concerning pain characteristics (intensity and spreading), the lowest frequency of fibromyalgia, as well as by a slightly older age. Group 2 was characterized by high "psychological strain" and by the most negative situation with respect to pain characteristics (intensity and spreading). Group 3 was characterized by high "social distress", the longest pain durations, and a statistically higher frequency of females. The frequency of three neuropathic pain conditions was generally lower in this group. Group 4 was characterized by high psychological strain, low "social distress", and high pain intensity. Conclusions The identification of these four clusters of chronic pain patients could be useful for the development of personalized rehabilitation programs. For example, the identification of a subgroup characterized mainly by high perceived "social distress" raises the question of how to best design interventions for such patients. Differentiating between clinically important subgroups and comparing how these subgroups respond to interventions is arguably an important area for further research.

Objectives: The aim of this open-label, non-randomized, clinical trial was to evaluate the feasibility of trialing ziconotide by intrathecal bolus injections. Material and Methods: Twenty-three patients, who had peripheral neuropathic pain refractory to pharmacological treatment and were under consideration for Spinal Cord Stimulation, received up to three ziconotide bolus injections according to a comprehensive algorithm. After a first injection of 2.5g, the patients progressed in the algorithm depending on the presence or absence of pain reduction and significant adverse events. A patient was considered a "responder" if experiencing pain reduction and no significant adverse event on two consecutive occasions at the same dosage. Results: We found a low proportion of responders (13%). However 30% of patients experienced greater than= 30% pain reduction on a least one injection, yielding a number needed to treat of similar to 3 for clinically significant pain relief. Pain intensity changed significantly over time (0-6h) (p = 0.047) after a mean ziconotide dose of 2.75 mu g. Adverse events were as expected, and no serious adverse event occurred. We did not find any statistical association between response to Spinal Cord Stimulation and response to ziconotide. Conclusions: Ziconotide bolus injection trialing seems feasible, but the proportion of responders in the present study was low. Adverse events were as expected, and no serious adverse event occurred. The predictive power of ziconotide bolus trialing remains unclear, and the pharmacological profile of ziconotide (slow tissue penetration due to high hydrophilicity) calls the rationale for bolus trialing into question.

In addition to central hyperexcitability and impaired top-down modulation, chronic inflammation probably plays a role in the pathophysiology of fibromyalgia (FM). Indeed, on the basis of both animal experiments and human studies involving the analysis of cytokines and other inflammation-related proteins in different body fluids, neuroinflammatory mechanisms are considered to be central to the pathophysiology of many chronic pain conditions. However, concerning FM, previous human plasma/serum and/or cerebrospinal fluid (CSF) cytokine studies have looked only at a few predetermined cytokine candidates. Instead of analyzing only a few substances at a time, we used a new multiplex protein panel enabling simultaneous analysis of 92 inflammation-related proteins. Hence, we investigated the CSF and plasma inflammatory profiles of 40 FM patients compared with CSF from healthy controls (n= 10) and plasma from blood donor controls (n= 46). Using multivariate data analysis by projection, we found evidence of both neuroinflammation (as assessed in CSF) and chronic systemic inflammation (as assessed in plasma). Two groups of proteins (one for CSF and one for plasma) highly discriminating between patients and controls are presented. Notably, we found high levels of CSF chemokine CX3CL1 (also known as fractalkine). In addition, previous findings concerning IL-8 in FM were replicated, in both CSF and plasma. This is the first time that such an extensive inflammatory profile has been described for FM patients. Hence, FM seems to be characterized by objective biochemical alterations, and the lingering characterization of its mechanisms as essentially idiopathic or even psychogenic should be seen as definitively outdated.

Visual capacity generally declines as people age, yet its impact on the visual search patterns along sections of different road during actual driving still remains undocumented. This onroad driving study simultaneously recorded 30 older drivers eye movement and precise vehicle movement trajectories. The vehicle positions were linked to every identified eye fixation for each individual driver, so that the locations of the drivers gaze origin in geospatial coordinates were obtained. Spatial distribution pattern of drivers eye fixations were then mapped and analysed. In addition, the associations between older drivers visual capacity (processing speed, divided and selective attention) and their eye fixation patterns in various driving manoeuvres were investigated. The results indicate that driving scenarios have a significant impact on older drivers visual patterns. Older drivers performed more frequent eye fixations at roundabouts, while they tended to fixate on certain objects for longer periods during straight road driving. The key findings show that the processing speed and divided attention of older drivers were associated with their eye fixations at complex right-turns; drivers with a lower capacity in selective attention performed less frequent eye fixations at roundabouts. This study has also demonstrated that visualisation and spatial statistics are effective and intuitive approaches to eye movement analysis.

The symptomatology of autism spectrum disorder (ASD) can make driving risky, but little is known about the on-road driving behaviour of individuals with ASD. This study assessed and compared the on-road driving performance of drivers with and without ASD, and explored how the symptomatology of ASD hinders or facilitates on-road driving performance. Sixteen drivers with ASD and 21 typically-developed drivers participated in the study. Drivers with ASD underperformed in vehicle manoeuvring, especially at left-turns, right-turns and pedestrian crossings. However, drivers with ASD outperformed the TD group in aspects related to rule-following such as using the indicator at roundabouts and checking for cross-traffic when approaching intersections. Drivers with ASD in the current study presented with a range of capabilities and weaknesses during driving.

Objective Fibromyalgia is associated with central hyperexcitability, but it is suggested that peripheral input is important to maintain central hyperexcitability. The primary aim was to investigate the levels of pro-inflammatory cytokines released in the vastus lateralis muscle during repetitive dynamic contractions of the quadriceps muscle in patients with fibromyalgia and healthy controls. Secondarily, to investigate if the levels of pro-inflammatory cytokines were correlated with pain or fatigue during these repetitive dynamic contractions. Material and Methods 32 women with fibromyalgia and 32 healthy women (controls) participated in a 4 hour microdialysis session, to sample IL-1 beta, IL-6, IL-8, and TNF from the most painful point of the vastus lateralis muscle before, during and after 20 minutes of repeated dynamic contractions. Pain (visual analogue scale; 0-100) and fatigue Borgs Rating of Perceived Exertion Scale; 6-20) were assessed before and during the entire microdialysis session. Results The repetitive dynamic contractions increased pain in the patients with fibromyalgia (P &lt; .001) and induced fatigue in both groups (P &lt; .001). Perceived fatigue was significantly higher among patients with fibromyalgia than controls (P &lt; .001). The levels of IL-1 beta did not change during contractions in either group. The levels of TNF did not change during contractions in patients with fibromyalgia, but increased in controls (P &lt; .001) and were significantly higher compared to patients with fibromyalgia (P = .033). The levels of IL-6 and IL-8 increased in both groups alike during and after contractions (Ps &lt; .001). There were no correlations between pain or fatigue and cytokine levels after contractions. Conclusion There were no differences between patients with fibromyalgia and controls in release of pro-inflammatory cytokines, and no correlations between levels of pro-inflammatory cytokines and pain or fatigue. Thus, this study indicates that IL-1 beta, IL-6, IL-8, and TNF do not seem to play an important role in maintenance of muscle pain in fibromyalgia.

Maintaining the musculoskeletal health of children using mobile information and communication technologies (ICT) at home presents a challenge. The physical environment influences postures during ICT use and can-contribute to musculoskeletal complaints. Few studies have assessed postures of children using ICT in home environments. The present study investigated the Rapid Upper Limb Assessment (RULA) scores determined by 16 novice and 16 experienced raters. Each rater viewed 11 videotaped scenarios of a child using two types of mobile ICT at home. The Grand Scores and Action Levels determined by study participants were compared to those of an ergonomist experienced in postural assessment. All postures assessed were rated with an Action Level of 2 or above; representing a postural risk that required further investigation and/or intervention. The sensitivity of RULA to assess some of the unconventional postures adopted by children in the home is questioned. (C) 2015 Elsevier Ltd and The Ergonomics Society. All rights reserved.

Objective: This pilot study explored the nature and quality of social experiences of children with Asperger Syndrome/High Functioning Autism (AS/HFA) through experience sampling method (ESM) while participating in everyday activities. Methods: ESM was used to identify the contexts and content of daily life experiences. Six children with AS/HFA (aged 8-12) wore an iPod Touch on seven consecutive days, while being signalled to complete a short survey. Results: Participants were in the company of others 88.3% of their waking time, spent 69.0% of their time with family and 3.8% with friends, but only conversed with others 26.8% of the time. Participants had more positive experiences and emotions when they were with friends compared with other company. Participating in leisure activities was associated with enjoyment, interest in the occasion, and having positive emotions. Conclusions: ESM was found to be helpful in identifying the nature and quality of social experiences of children with AS/HFA from their perspective.

Shared zones are a contemporary traffic zone that promotes equality between multiple road users and efficiently utilizes available space, while simultaneously maintaining safety and function. As this is a relatively new traffic zone, it is important to understand how pedestrians navigate a shared zone and any potential challenges this may pose to individuals with impairments. The aim of this study was to utilize eye-tracking technology to determine fixations and fixation duration on traffic relevant objects, non-traffic relevant objects, and eye contact, in 40 individuals with and without Autism Spectrum Disorder (ASD) in a shared zone and a zebra crossing. It was assumed that individuals with ASD would make less eye contact in the shared zone compared to the group of typically developing adults. A total of 3287 fixations across the shared zone and zebra crossing were analysed for areas of interest that were traffic relevant, non-traffic relevant, and eye contact, and for fixation duration. Individuals with ASD did not display any difference in terms of eye contact in the shared zone and the zebra crossing when compared to the controls. All pedestrians were more likely to look at traffic relevant objects at the zebra crossing compared to the shared zone. Individuals with ASD had an overall shorter fixation duration compared to the control group, indicating people with ASD either process information quickly, or they do not process it for long enough, although these findings require further investigation. While shared zones have many benefits for traffic movement and environmental quality, it appeared that pedestrians displayed safer road crossing behaviours at a zebra crossing than in a shared zone, indicating that more education and environmental adaptations are required to make shared zones safe for all pedestrians.

Sleep problems are common in children with autism spectrum disorder (ASD). This meta-synthesis collated eight previously published systematic reviews examining the efficacy of sleep interventions in children with ASD in an attempt to present a clear analysis of trialed interventions. The collated reviews consider five major groups of sleep interventions for children with ASD: melatonin therapy, pharmacologic treatments other than melatonin, behavioral interventions, parent education/education programs, and alternative therapies (massage therapy, aromatherapy, and multivitamin and iron supplementation). These eight reviews were based on 38 original studies and address the efficacy of interventions across 17 sleep problem domains. The results of this meta-synthesis suggest that no single intervention is effective across all sleep problems in children with ASD. However, melatonin, behavioral interventions, and parent education/education program interventions appear the most effective at ameliorating multiple domains of sleep problems compared with other interventions. Due to the heterogeneous causative factors and presentations of disordered sleep, further research into the effectiveness of sleep interventions may target specific phenotypic subgroups rather than a broad analysis across the general ASD population. Similarly, future research needs to consider the efficacy of different polytherapeutic approaches in order to provide clinicians with evidence to inform best practice. In the meantime, this review supports clinicians decision making for a majority of the identified sleep problems in the ASD population.